Age-related macular degeneration (AMD) is the most common cause of severe vision loss among individuals over age 50 in the U.S. The socioeconomic impact is considerable, and is expected to become greater as the U.S. population ages. Unfortunately, treatment options remain limited because the etiology of this devastating disease remains unknown. Considerable evidence implicates a combination of genetic, environmental, and biological factors in the pathogenesis of AMD as such suggested genetic effect involves the ATP-binding transporter (ABCR) gene. We thus hypothesize that underlying susceptibility gene(s) are critical to the development of AMD, and likely interact with environmental factors to trigger both the development and progression of the disease. The purpose of this study is to elucidate the genetic susceptibility to the development of AMD and to analyze the interaction of these genes with environmental influences. We will use both candidate gene and genomic screening approaches to identify these genes. Already identified genetic and environmental risk factors will be evaluated and current statistical methodologies will be adapted to examine the possible interactions. Multiplex (greater than 1 AMD affected/family) families will be recruited for the genetic analyses and detailed risk factor information will be collected on all study participants. Family-based association methods will be used to evaluate candidate genes, environmental risk factors and gene- gene and gene-environment interactions. The information derived from this study will further our understanding of this complex disease. The identification of specific susceptibility genes and evaluation of gene-environment interaction will be crucial for future studies in unraveling the etiology of AMD and developing better treatments.